Drug synergy scoring using minimal dose response matrices

Abstract

Objective: Combinations of pharmacological agents are essential for disease control and prevention, offering many advantages over monotherapies, with one of these being drug synergy. The state-of-the-art method to profile drug synergy in preclinical research is by using dose-response matrices in disease-appropriate models, however this approach is frequently labour intensive and cost-ineffective, particularly when performed in a medium- to high-throughput fashion. Thus, in this study, we set out to optimise a parameter of this methodology, determining the minimal matrix size that can be used to robustly detect and quantify synergy between two drugs. Results: We used a drug matrix reduction workflow that allowed the identification of a minimal drug matrix capable of robustly detecting and quantifying drug synergy. These minimal matrices utilise substantially less reagents and data processing power than their typically used larger counterparts. Focusing on the antileukemic efficacy of the chemotherapy combination of cytarabine and inhibitors of ribonucleotide reductase, we could show that detection and quantification of drug synergy by three common synergy models was well-tolerated despite reducing matrix size from 8x8 to 4x4. Overall, the optimisation of drug synergy scoring as presented here could inform future medium- to high-throughput drug synergy screening strategies in pre-clinical research.

Inhibiting the transcription and replication of Ebola viruses by disrupting the nucleoprotein and VP30 protein interaction with small molecules

“…Considering the antiviral EC 50 of the four drugs alone in the minigenome system, we established a drug cross design to evaluate the synergies and sensitivity of antiviral activity of the two drug combinations. Huh7-4P cells were treated with increasing doses of combination drugs in a 7 × 7 concentration checkerboard format [46,47]. To fully understand the synergy of the drug combination, avoid the calculation deviation caused by a certain calculation mode, HSA, Bliss, Loewe and ZIP synergy metrics were compared for combinations and single agents calculated with the SynergyFinder tool [48].…”